Cutaneous metastases of pancreatic carcinoma to the labia majora: A case report and review of literature.

BACKGROUND: Cutaneous metastases originating from pancreatic cancer are relatively rare. The most common reported site of metastasis is the umbilicus, and this manifestation is known as the Sister Mary Joseph's nodule. Non-umbilical cutaneous metastases are far less common, with only a few cases reported in the literature. Our case is the first case report, to our knowledge, on metastasis involving the labia majora and flat papules. CASE
SUMMARY: A 49-year-old Chinese female patient presented with a number of red, swollen papules on the vulva for 2 mo. Histological examination of the labia majora lesion revealed metastatic adenocarcinoma. The serum levels of tumor biomarkers CA199, CA242, and CA125 were significantly elevated. B-mode ultrasound-guided needle biopsy of the pancreas demonstrated moderately and poorly differentiated adenocarcinoma. The patient finally declined treatment for financial reasons and died 3 mo later.
CONCLUSION: Metastatic cutaneous lesions could indicate pancreatic cancer. Serum levels of tumor biomarkers may aid in diagnosing metastatic pancreatic adenocarcinoma. ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.

Core Tip: Cutaneous metastasis from pancreatic cancer is uncommon. The most common site of the skin lesion is the umbilicus. The majority of skin lesions are singular, particularly in patients exhibiting the Sister Mary Joseph’s nodule. We describe an unusual case of flat papules on the labia majora that metastasized from pancreatic cancer. The lesion was the first sign of metastatic disease, and serum levels of CA199, CA242, and CA125 were also elevated. We report this case to improve the understanding of cutaneous metastasis of pancreatic cancer and emphasize the importance of serum levels of CA199, CA242, and CA125 in diagnosing pancreatic cancer.

INTRODUCTION

Pancreatic cancer is one of the most lethal human malignancies and is often diagnosed late in the course of the disease. Cutaneous metastases originating from pancreatic cancer are relatively rare. The most common reported site of metastasis is the umbilicus, and this manifestation is known as the Sister Mary Joseph’s nodule. Non-umbilical cutaneous metastases are far less common, with only a few cases reported in the literature. To our knowledge, there are no previous reports on metastasis involving the labia majora and flat papules. This report describes a case of cutaneous pancreatic metastases on the labia majora in a Chinese woman, and a review of previously reported non-umbilical cutaneous pancreatic carcinoma metastases (by conducting a detailed PubMed search). Furthermore, an analysis of 34 reported cases of non-umbilical cutaneous metastasis from pancreatic cancer was conducted with regard to the clinical characteristics.

CASE PRESENTATION

Chief complaints

A 49-year-old female patient with a number of red, swollen papules on the vulva for 2 mo was referred to our department.

History of present illness

The patient had developed red, swollen papules on the vulva 3 mo previously. She attended a local hospital, where she was diagnosed with contact dermatitis and took regular anti-allergy treatment. There was no obvious improvement in her symptoms. Erythema gradually affected the abdomen and lower extremities. The patient had experienced intermittent shortness of breath and coughed up white sputum during this period.

History of past illness

The patient had experienced hypertension for 2 years and had a history of sulfonamide allergy.

Personal and family history

There was not a personal or family history of pancreatic cancer.

Physical examination

Physical examination revealed diffuse erythema and swelling on the chest, abdomen, and vulva; right leg edema; and a number of flat skin-colored or gray papules on the labia majora (Figure 1).

Figure 1

Photographs of our patient. A: Diffuse erythema and swelling on the chest, abdomen, and right leg; B: Edema and a number of flat skin-colored or gray papules on the labia majora.

Laboratory examinations

Routine laboratory testing revealed that the patient was human immunodeficiency virus (HIV) negative; the results of blood and urine tests and levels of renal and hepatic markers and antinuclear antibodies were within the normal ranges. There was a remarkable elevation in the serum concentrations of tumor markers, comprising cytokeratin 19 (8.98 g/L; normal: < 5 µg/L), CA242 (> 500 U/mL; normal: < 20 U/mL), CA125 (52.41 U/mL; normal: < 35 U/mL), and CA199 (726.54 U/mL; normal: < 37 U/mL).

Imaging examinations

An ultrasound scan showed bilateral mammary gland hyperplasia, no other gynecological abnormalities, and right leg lymphedema. A chest computerized tomography (CT) scan revealed inflammation, with patterns of interstitial change scattered across both lungs and a little pleural effusion in the left lung. An abdominal CT scan demonstrated many enlarged lymph nodes, associated with the abdominal aorta, bilateral iliac artery, and bilateral inguinal region, as well as changes in the pancreatic and peripancreatic morphology. A positron emission tomography (PET)-CT scan showed increased metabolic activity in the tail of the pancreas and multiple enlarged lymph nodes throughout the body, as well as subcutaneous tissue edema (Figure 2).

Figure 2

Positron emission tomography-computed tomography scan showing increased metabolic activity. A: The tail of the pancreas; B: Mediastinum, hilus of the lung, and postperitoneal lymph nodes.

Further diagnostic work-up

A punch biopsy was performed on the abdomen and labia majora lesions. The abdominal epidermis was normal, and there were dilated small blood vessels and lymph vessels in the dermis, and small quantities of infiltrating lymphocytes. Histological examination of the labia majora papules showed nests of moderately differentiated atypical cells partly forming adenomatous structures in the collagen bundles of the dermis and lymphangiectasia (pathologic dilation of the lymph vessels) in the dermis (Figure 3). The immunohistochemical staining results (Figure 4) were as follows: CK7 (+), panCK (+), CK19 (+), CA19-9 (+), CDX-2 (+), CK20 (+), D2-40 (-), and P63 (-), which is consistent with a possible pancreatic source of the metastasis.

Figure 3

Pathology of cutaneous metastasis. A: Histological examination of the labia majora papule showing nests of moderately differentiated atypical cells partly forming adenomatous structures in the collagen bundle of the dermis and lymphangiectasis in the dermis [hematoxylin-eosin (HE) staining, × 40]; B: Dermis occupied by mass of numerous tumor cells (HE staining, × 200).

Figure 4

Neoplastic glands showing a positive reaction to immunohistochemical staining (100 ×). A: CK7 (+); B: panCK (+); C: CK19 (+); D: CA199 (+); E: CK20 (+); F: CDX-2 (+).

In addition, a large amount of milky fluid was drained from the skin biopsy sites. While the serum triglyceride level was normal, the level in the fluid was 1.55 mmol/L, indicating lymphocytosis. Neither bacteria (including Mycobacterium tuberculosis) nor fungi were found in the fluid. According to the laboratory and histopathologic findings, a diagnosis of chylous reflux fluid was made.

Thereafter, B-mode ultrasound-guided needle biopsy of the pancreas demonstrated moderately and poorly differentiated adenocarcinoma (Figure 5).

Figure 5

B-mode ultrasound-guided needle biopsy of the pancreas showing the moderately and poorly differentiated adenocarcinoma (hematoxylin-eosin staining, × 200).

FINAL DIAGNOSIS

According to the clinical manifestations and histopathologic findings, a diagnosis of metastatic pancreatic carcinoma was established.

TREATMENT

The patient declined treatment for financial reasons.

OUTCOME AND FOLLOW-UP

The patient died 3 mo later.

DISCUSSION

Cutaneous metastases are rare, occurring in 0.7%-9.0% of all patients with cancer[1]. Breast, lung, and colon cancer are the most frequent origins of cutaneous metastases.

Pancreatic cancer is one of the most lethal cancers, with a 5 year survival rate of 5%. Owing to a lack of early clinical features and the fulminant disease course, early diagnosis is difficult and the metastasis rate is high, with a median overall survival of 5 mo[2]. Pancreatic cancer is often known to metastasize via the lymphatic system, with direct invasion at an early stage and hematogenous dissemination at a later stage. The incidence of cutaneous metastases is significantly more frequent for cancers of the pancreatic body and tail than for pancreatic head cancer[3].

The most frequent organs involved in the metastasis are the liver, peritoneum, lungs, bones, and brain[2]. Indeed, only 2% of the first metastases from pancreatic cancer are cutaneous metastases, making cutaneous metastases relatively rare[4]. The most common site of cutaneous metastasis from the pancreas is the umbilicus, and this manifestation is known as Sister Mary Joseph’s nodule[5]. Horino et al[6] reviewed 42 reported cases of pancreatic metastasis from 1950 to 2011, and included only 14 cases of non-umbilical cutaneous metastasis, involving the head, neck, and truncal region. The patients with pancreatic metastasis had such symptoms as subcutaneous nodules (in 26 patients) and inflammatory erythema (in 3 patients).

We collected all case reports of non-umbilical metastatic skin cancer from 1950 to 2020 on the electronic PubMed database (www.ncbi.nlm.nih.gov/pubmed; up to July 2020) by searching using Medical Subject Headings (www.nlm.nih. gov/mesh) and keywords, and by limiting the search to human studies (Table 1)[1-4,6-30]. The terms pancreatic cancer, pancreatic neoplasm, pancreatic carcinoma, cutaneous metastasis, and skin metastasis were used. The abstracts were reviewed, and articles that were associated with umbilical metastasis were excluded. Duplicate references as well as repeated publications were discarded. All of the studies that were considered to be eligible were retrieved and the final selection was based on the full article.

Table 1

Review of case reports of nonumbilical cutaneous metastasis from pancreatic cancer

	Ref.	Age (yr)	Sex	Appearance	Metastatic site	Primary	Year
1	Edelstein et al[10]	60	M	Cellulitis	Face, neck	NA	1950
2	Sakai et al	47	M	Herpes zoster-like	No details	Head	1969
3	Sironi et al[12]	72	M	Nodule	Right thigh	Head	1991
4	Lookingbill et al[13]	No details	No details	Nodule	Abdomen	No details	1993
5	Taniguchi et al[4]	63	F	Erythematousplaques, nodule	Left axilla, chest	No details	1994
6	Ohashi et al	79	M	Nodule	Neck, chest, abdomen	No details	1995
7	Ohashi et al	65	M	Nodule	Back	No details	1995
8	Fukui et al	49	M	Nodule	Face, chest	No details	1995
9	Puri et al[14]	45	M	Nodule	Scalp, face, neck, back	No details	1995
10	Nakano et al[15]	80	M	Nodule	Occipital scalp	Tail	1996
11	Miyahara et al[16]	43	M	Nodule	Scalp	Uncus	1996
12	Miyahara et al[16]	65	M	Nodule	Mentum	Uncus	1996
13	Horino et al[17]	65	F	Nodule	Chest wall	Head	1999
14	Flórez et al[18]	48	M	Nodule	Buttock	Head	2000
15	Gawrieh et al[19]	45	F	Nodule	Temporal scalp	No details	2002
16	Takeuchi et al[3]	77	M	Nodule	Left axilla	Tail	2003
17	Otegbayo et al[20]	59	M	Nodule	Face, chest, abdomen, back	No details	2005
18	Jun et al[21]	68	M	Nodule	Right forearm, chest	Body, tail	2005
19	Ambro et al[22]	63	M	Nodule	Scalp	Ductal	2006
20	Takemura et al[23]	85	M	Nodule	Left temple	No details	2007
21	Hafez et al[24]	55	F	Nodule	Neck	Head	2008
22	Kimura et al	50	M	Nodule	Lateral abdomen	Body	2008
23	van Akkooi et al[25]	59	M	Nodule	Scalp	No details	2010
24	Bdeiri et al[1]	59	F	Nodule	Scalp	Tail	2010
25	Pontinen et al[26]	67	F	Nodule	Lower abdomen	Tail	2010
26	Saif et al[27]	46	F	Nodule	Chest, abdomen, right supraclavicular area	No details	2011
27	Horino et al[6]	58	F	Nodule	Lower abdomen	Body	2012
28	Horino et al[6]	65	F	Nodule	Lower abdomen	Tail	2012
29	Bdeiri et al[1]	70	F	Nodule	Scalp	Tail	2013
30	Kaoutzanis et al[28]	43	M	Nodule	Scalp	Head	2013
31	Zhou et al[2]	76	F	Nodule	Scalp, chest, abdomen	Tail	2014
32	Shin et al[29]	60	M	Mass	Left hip	Body	2015
33	Kotsantis et al[11]	62	M	Edema	Scrotum, trunk, chest wall	Head	2017
34	Ito et al[30]	71	F	Ulcer	Scalp	Tail	2020

NA: Not available; F: Female; M: Male.

Our case is unique in that the cutaneous pancreatic cancer metastases were found on the labia majora. Our patient had papules on the labia majora, with diffuse swelling on the skin of the chest, abdomen, and vulva. In addition, there was oozing of chyle from the skin biopsy sites.

Chyle originates in the bowel lacteals (lymphatic capillaries that absorb dietary fats), is absorbed by the intestinal lymphatic vessels, passes through the collecting lymphatic vessels into the intestinal trunk (truncus intestinalis), and then passes through the cisterna chyli and thoracic duct to the bloodstream. If the reflux is obstructed, chylous reflux occurs; the chyle flows backward or leaks into the serosal cavity, external genitalia, lower limbs, etc. Chylous reflux is divided into primary and secondary types. Secondary chylous reflux is usually caused by neoplasia, trauma, inflammation, or surgery[7]. According to the PET-CT scan, the metastatic cancer cells may have traveled to the labia majora via the lymphatic pathways. The abnormal lymphatic system, caused by tumor metastasis, may have been the underlying cause for the backflow of chyle to the skin. The patient was advised to undergo lymphangiography to confirm this, but declined for financial reasons.

The serum levels of tumor biomarkers CA199, CA242, and CA125 were significantly elevated in our case. It has been shown that the sensitivity and specificity of CA199 for diagnosing pancreatic cancer are 77% and 88%, respectively. Ozkan et al[8] revealed that CA242 was significantly increased in 75% of pancreatic cancer patients. To sum up, Mao et al[9] suggested that assessment of the combination of CA199, CA242, CEA, and CA125 levels is a simple, noninvasive, and effective method for early diagnosis of pancreatic cancer.

We present a case of pancreatic adenocarcinoma metastasizing to the vulva, with a number of flat papules. This condition is extremely rare and easy to misdiagnose.

CONCLUSION

Cutaneous metastasis from pancreatic carcinoma is a rare finding and mostly occurs around the umbilicus. Subcutaneous nodules are the most common clinical manifestation. To our knowledge, we describe the first case of cutaneous pancreatic metastasis to the vulva, with a number of flat papules. Clinicians should be aware of the possibility of metastatic cutaneous lesions in pancreatic adenocarcinoma and screen for tumor markers as promptly as possible.